Esters of hydroxymethyl-dioxabicyclononene

ABSTRACT

WHEREIN Z1 represents a free or an esterified hydroxy group, are produced by eliminating an ester group from a monoester or a diester of 2-hydroxymethyl-2,4-dioxabicyclo(3,3,1)nonane-7-ol; they are intermediates for the synthesis of prostaglandins. Compounds of formula

United States Patent 1 1 Woodward [4 1 Aug. 19, 1975 I ESTERS OF HYDROXYMETHYL- DIOXABICYCLONONENE [75] Inventor: Robert Burns Woodward,

Cambridge. Mass.

[73] Assignee: Ciba-Geigy Corporation, Ardsley,

221 Filed: Feb. 2, 1973 21 1 Appl. No.: 329,255

OTHER PUBLICATIONS Jerry March, Advanced Organic Chemistry: Reactions, Mechanisms and Structure (1967) pp. 757-758.

R. A. Bartsch, .Iour. Org. Chem., Vol. 35, No. 4, Apr. I970, PP. IO23I()25.

Primary ExaminerNorma S. Milestone Attorney, Agent, or Firm.loseph G. Kolodny; John J. Maitner; Theodore O. Groeger 57 1 ABSTRACT Compounds of formula wherein Z represents a free or an esterified hydroxy group, are produced by eliminating an ester group from a monoester or a diester of 2-hydroxymethyI-2,4- dioxabicyclo[3,3,l ]nonane-7-0I; they are intermediates for the synthesis of prostaglandins.

4 Claims, No Drawings (III) wherein Z, represents a free or an esterified hydroxy group, their optical antipodes, racemic mixtures of the compounds, and to a method process for their manufacture.

The significance of the present invention resides in the manufacture from readily accessible and inexpensive starting materials of intermediate products which can be used for the stereospecific synthesis both of known, naturally occurring prostaglandins as well as of new synthetic prostaglandins. The individual steps proceed with high yields. The new intermediate products are therefore suitable for carrying out the synthesis of the cited prostaglandins on an industrial scale. I

From these intermediate products it is possible to manufacture first and foremost the prostaglandins of the F -series which are characterised by an optionally unsaturated a-alkanecarboxylic acid in 8-position, an a-hydroxyolefine grouping in 12-position and two oz-hydroxy groups in 9,1 l-position. Secondly, it is possible to use the new compounds as intermediate products for the manufacture of prostaglandins of the E, A .and B series, and furthermore of derivatives and homologs of prostaglandins.

The biological activity and the importance of prostaglandins in medicine are known and described, for example, by M. P. L. Caton in Progr. Med. Chem. 8, 317 (1971 The standard prostaglandin numbering used herein is derived from prostanoic acid which has the following structure:

1112 l3 l4 l5 16 l7 l8 19 In the above formulae, as well as in those hereinafter, dotted lines indicate substituents which are situated behind the plane defined by thecyclopentane ring; these substituents are denoted by a. Thickly drawn lines indicate substituents which are in front of this plane; these are denoted by B. Substituents linked by wavy lines can be in the aor fi-configuration. The standard prostaglandin nomenclature is used as illustrated hereinabove in the formula of prostanoic acid. For the standard prostaglandin nomenclature compare also S. Bergstrom, Science, 157, 382 (1967), M. P. L. Caton, Progr. Med. Chem. 8, 317, (1971) and Niels Andersen, Annals of the New York Academy of Sciences, Vol. 180, S. 14, Apr. 30, 1971.

The stereospecific manufacture of the cited prostaglandins using the new compounds according to the invention is carried out by a new and original multi-step process. The following scheme reproduces, for example, the synthesis of natural prostaglandins F (PGF (XIlla) and F (PGF (XIllb).

Z Z CH i! a 5 4 l :I

N c I L 1;;- H 2 I b 0 (D8 HQ OH H6 6 (VIII) (V!) (v) 1 V 4 OH 0 3. H o) 14. H CIOOH I c I. g cw" o s R R R R I OH i (X (Lb/C) i in the formulae Xa, Xla, Xlla and Xllla, R represents the group in the formulae Xb, Xlb, Xllb, Xlllb, R represents the group and in the formula Xc, R represents the group 1st. Step Cis-cyclohexane-1,3,5-triol [K. H. Steinacker and H. Stetter, Chem. Ber. 85, 451 (1952)] is converted with glyoxylic acid, or a reactive functional derivative thereof, e.g. its hydrate, an ester or an acetal, into the compound of the formula I, in which X, and X together represent the 0x0 group. The reaction is advan tageously carried out in the presence of an acid catalyst, e.g. p-toluenesulphonic acid, in an inert solvent, e.g. benzene or ethylene glycol dimethyl ether, at .a temperature of about 20C to the boiling point of the solvent employed.

The compound of the formula I, in which X, represents a hydrogen atom and X represents the hydroxy group, is formed when ciscyclohexane-1,3,5-triol is reacted under similar conditions with glyoxal, or a reac tive functional derivative thereof, e.g. the hydrate or one of its acetals.

2nd. Step A compound of the formula I is converted by reduction into a compound of the formula ll, wherein Z, and Z are hydroxy groups. Complex hydrides, e.g. lithium aluminium hydride, lithium borohydride or sodium borohydride, can be used as reducing agents. The re duction is carried out at reduced or slightly elevated temperature, preferably between about 10C and C, in a suitable solvent. Lithium aluminium hydride or lithium borohydride are preferably used in etheral liquids, such as diethyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, tetrahydrofuran or dioxan. it is also possible to carry out the reduction with sodium borohydride in lower alkanols, such as methanol, ethanol, isopropanol or tert. butanol, or also in water.

3rd. Step The compound falling under the formula II manufactured in the 2nd. step, in which Z, and Z are hydroxy groups, is converted with methanesulphonyl chloride and pyridine into its dimesylate, which also falls under the formula II. The reaction can be carried out in pyridine as solvent and maintaining low temperatures, about 20C. According to another esterification method, it is possible to use triethylamine as proton acceptor and methylene chloride as solvent.

4th. Step The compound of the formula ll, wherein Z, and Z represent esterified hydroxy groups, e.g. mesyloxy groups, is converted into the compound of the formula III, in which Z has the same meaning as in the starting material, by splitting off H-Z with a base to form the double bond. Organic or inorganic bases can be used as bases. Particularly suitable bases are 1,5- dia-zabicyclo [5 ,4,0]undec-5-ene. which can be used in e.g. dimethyl sulphoxide at a temperature of about 1 C, or tetra-n-butylammonium fluoride, which can be used e. g. in dimethyl formamide at a temperature of about 60C. Particularly preferred are alkali hydroxides, such as potassium hydroxide, e.g. in lower alkanols, such as isopropanol, at elevated, e.g. reflux, temperature.

In the reaction according to this step the racemate is formed, which can be used as such in the next step. If desired, the racemate can be resolved into both its optical antipodes by one of the methods described hereinafter.

5th. Step The bicyclic compound of the formula Ill, wherein Z is for example a mesyloxy group, or the corresponding racemate, can be converted in surprising manner into the tricyclic compound of the formula IV, wherein Z is a hydroxy group. This reaction is surprising because normally the formation of two six-membered rings, but not of a five-membered and a seven-membered ring, would be expected.

The reaction is preferably carried out in a watermiscible solvent, e.g. in ethylene glycol dimethyl ether/water mixture, in the presence of potassium carbonate at a temperature of about 80C.

The reactions of the 4th. and 5th. steps can also be carried out in one operation by treating a diester falling under the formula II, e.g. dimesylate, with a solution of hydroxyl ions, e.g. with an alkali solution, such as a potassium hydroxide solution, in a solvent, such as in a lower alkanol, e.g. isopropanol. If desired, the crude compound of the formula IV, or its racemate, can be purified via its acetate.

If a start is made from the racemit mixture, consisting of the compound of the formula III and its optical anti pode, there is obtained the racemit mixture consisting of the compound of the formula IV and its optical antipodes. The separation into the antipodes can also be effected in this step as described further on. However, instead of starting from the racemate, it is also possible to start from the optically active compound of the formula III, in the process of which the optically active compound of the formula IV is obtained directly.

6th. Step The secondary alcohol of the formula IV, wherein Z, is a hydroxy group, or its racemate, is converted in the usual manner with methanesulphonyl chloride and a suitable base, eg. triethylamine or pyridine, in a suitable solvent, e.g. in methylene chloride, into the compound of the formula IV, in which 2;, represents the mesyloxy group. If desired, it is also possible in this step to effect the resolution into the optical antipodes, as described later in more detail.

7th. Step The methylsulphonyl ester of the formula IV, or its racemate, is converted into the unsaturated compound of the formula V, or its racemate, by splitting off methanesulphonic acid. The splitting off is effected in the presence of a base, e.g. potassium tert. butylate, or 1,5-

diazabicyclo [5,4,0]undec-5'ene. in a solvent, e.g. dimethyl sulphoxide, or, preferably, in the presence of an alkali hydroxide, such as potassium hydroxide, in a boiling lower alkanol, such as isopropanol.

8th. Step The unsaturated compound of the formula V, or its racemate, is oxidised with e.g. a hydroperoxide, for example, a peracid, such as m-chloroperbenzoic acid, or, preferably, with a peroxyimidic acid, for example peroxybenzimidicacid, to a mixture consisting of the a-epoxide of the formula VI and the corresponding B-epoxide, or the racemates thereof, preferably at slightly elevated temperature or elevated temperature, e.g. between about 0C and 50C. When using a peracid, such as m-chloroperbenzoic acid, the B-epoxide is formed as main product; when using a peroxyimidic acid, such as peroxybenzimidic acid, which can be prepared from an optionally substituted benzonitrile or lower alkyl nitrile with hydrogen peroxide in the presence of a base, such as an alkali metal bicarbonate, e.g. potassium bicarbonate, in a solvent, such as a lower alkanol, e.g. in methanol, surprisingly more 01- than B-epoxide is obtained. Both epoxides can be separated, for example, by chromatography, or further processed as a mixture. The separated B-epoxide, or its racemate, can be reduced with a complex hydride, e.g. with lithium aluminum hydride, in a solvent, e. g. in tetrahydrofuran, to an alcohol of the formula IV, or its racemate. The B-epoxide is thereby led back into the process. In this step it is also possible to perform any desired racemate separation.

9th. Step In an a-epoxide of the formula VI, or its racemate, it is possible to open the epoxide ring, for example, with ammonia in a solvent, such as water, at elevated temperature, e.g. between about 50C and C, optionally under pressure, in the process of which a compound of the formula VII, its racemate or acid addition salts thereof, are formed. The epoxide ring is opened in such a way that the 4,8-amino-5a-hydroxy compound of the formula VII, or-its racemate, is formed. The possible isomeric 5/3-amino-4a-hydroxy compound is not obtained, or is obtained in undetectably small amounts.

If desired, it is possible to resolve an optionally resulting racemate.

10th. Step A compound of the formula VII, its racemate or an acid addition salt thereof, can be converted in the presence of a lower alkanol, such as methanol, by treatment with an acid, for example a hydrohalic acid, e.g. hydrochloric acid, into a compound of the formula VIII, wherein Z, represents lower alkoxy, e.g. methoxy, its racemate or an acid addition salt thereof. The reaction can be carried out at slightly reduced or elevated temperature, e.g. between about 0 and 50C. It is also possible here to resolve an optionally resulting racemate.

Steps 8-10, i.e. the epoxidation of an olefine, amininolysis of the epoxide and splitting of the 6-10 bond in the tricyclic skeleton, can also be carried out in another sequence. For example, in an oz-epoxide of the formula VI, or its racemate, the 6-10 bond can be split according to the reaction conditions of the 10th. step, and in the resulting 2,3-endoepoxy-4-endo-hydroxy-8-alkoxy- 7-oxabicyclo[4,3,0lnonane of the formula VI, or in the racemate thereof, the epoxy grouping can be aminolysed according to the method of the 9th. step, in the process of which a compound of the formula VIII, or its racemate, is formed. Furthermore, in a tricyclic olefine of the formula V, or in its racemate, it is possible to cleave the 6-10 bond according to the reaction conditions of the 10th. step and, in the resulting bicyclic olefine of the formula V, or in its racemate, to epoxidise the double bond according to the method of the 8th. step, whereupon once again a compound of the formula VI, or its racemate, is obtained.

1 1th. Step From the compound of the formula VIII, its racemate or an acid addition salt thereof, it is possible to split off the amino group, in the process of which a ring contraction simultaneously takes place and an aldehyde of the formula IX, wherein Z, is lower alkoxy, such as methoxy, and Z is hydroxy, or its racemate, is formed. The splitting off can be performed by diazotisation, e. g. with nitrous acid, prepared in situ from one of its salts, such as sodium nitrite, and an acid, such as acetic acid, or with an anhydride of nitrous acid, such as dinitrogen tetroxide, in a solvent, such as water, or in an ethereal solvent, such as ethylene glycol monomethyl ether, preferably at reduced temperature, e.g. between about -l and +50Cv If desired, it is also possible to resolve an optionally obtained racemate by one of the methods described later herein, into both its optical antipodes.

12th. Step The aldehyde of the formula IX, wherein Z represents methoxy and Z represents hydroxy, or its racemate, can be used for the synthesis of primary steps which lead either to prostaglandin F or also to F a The compound of the formula Xa can be manu factured therefrom by reaction with the Wittig reagent which is prepared in the conventional manner from 2- (S )-hydroxy-n-heptyltriphenylphosphonium iodide and methyl lithium IE. .1. Corey et al., Ann. New York Acad. Sci. I80 33 (1971)]. The reaction takes place at temperatures between about 78C and about C in tetrahydrofuran or ethylene glycol dimethyl ether, in the process of which a transdouble bond is formed. The compound of the formula Xb can be manufactured therefrom in analogous manner by using the known Wittig reagent from cis-2-(S)-hydroxy4-n-heptenyltriphenylphosphonium iodide [13. J. Corey et al., J. Am. Chem. Soc. 93, 1490 (1971)].

If the racemate consisting of the compound of the formula VI and its optical antipodes is used as starting material, there is obtained an diastereoisomer mixture which, with the aid of physicochemical separating operations, can be separated or further processed as such.

If instead of Z-(S)-hydroxy-n-heptyl-triphenylphosphonium iodide there is used racemic Z-hydroxy-nheptyl-triphenylphosphonium iodide or the corresponding heptenyl derivatives, once again a diastereoisomer mixture is obtained which likewise can either be further processed or separated by the aid of physicochemiez-l separating operations. The saint \li'lNlLl'C oisomt" mixture is obtained I using instead of the I hydroxy-heptyl-or Z-hydroxy-heptenylphosphonium compounds at corresponding loxo-hcptyl or 2-oxoheptenyl derivative, cg. l"triphenylphosphoniuni L heptanone-bromide or the ltriphenylph isphoranylidcnel heptanone prepared theim'from with sodium hydrogen carbonate [M. Miyano and C. R. Dorn, Tetrahedron Letters 1615 1969)], and reducing the resulting ketones of the formula Xe with a complex hydride, such as sodium borohydride. The two racemates obtained thereby can again either be further processed as such or resolved into their respective two optical antipodes with optically active auxiliary products by methods later described herein.

13th. Step The cyclic acetals of the formulae Xa and Xb, wherein Z represents e.g. methoxy and Z represents hydroxy, their racemates or the corresponding diastereoisomer mixtures, are hydrolysed under acid conditions to the compound of the formula Xla or Xlb or to their racemates.

These compounds can be in the form of the free aldehyde or in that of the cyclic hemiacetal of the formula XII. In using optically active starting material of the formula Xa or Xb, the trihydroxy compounds already contain all steric prerequisites for their conversion in the next step into the natural, optically active PGF a and PGI- a If a start is made from the racemate of a compound of the formula Xa or Xb, the racemate is obtained which consists of a mixture of the compound of the formula Xla or XIb and the optical antipodes thereof. The separation of the racemate can be effected by one of the conventional processes later described herein. By starting from the diastereoisomer mixtures which may be obtained in the 12th. step, once again diasteroisomer mixtures are obtained which can be fu rther processed as such or resolved analogous to the methods mentioned in the 12th. step.

14th. Step The compounds of the formula Xla or Xlb, corresponding hemiacetals of the formula XIla or Xllh or also the corresponding raeemates or diastereoisomer mixtures, are finally converted with the Wittig reagent from 5-triphenylphosphonovaleric acid [H J. Corey, T. K. Schaaf, W. Huber, U, Koelliker and N. M. Weinshenker, J. Amer. Chem. Soc. 92, 397 (1970) and 91, 5675 (1969)] in dimethyl sulphoxide [R. GreenwaltL M. Chaykowsky and E. J. Corey, J. Org. Chem. 28, 1128 (1963)] into the prostaglandin F of the formula XIIIa or P of the formula Xlllb, Preferably a cis-double bond is formed in this reaction.

The natural, optically active PGF or F is ohtained directly by using optically active starting material of the formulae Xla or Xlb, Xlla or Xllb. By starting from the racemate of the compound of the formula Xla or Xlb or XIIa or Xllb, a racemate is obtained which consists of a mixture of natural PGF and PGF and the optical antipodes thereof. The race mate separation can be effected by one of the conven tional methods later described herein.

If a start is made from the diastereoisomer mixtures which may be obtained in the 13th. step, once again mixtures are obtained which consist of the naturally oe curring prostaglandin F l a and then diaster eoisomers. which can aseul a such as mentioned in the 12th. Ship.

'Iiie racemates mentioned hezmn'fwefore can be re solved into their optical antipodes by methods which are known per so.

one of these methods consists in reacting a racemate with an opticall aetivi: auxiliar su stance. separating the resulting mixture of two diastereoisomer compounds with the aid of appropriate physicochemical methods and then resolving the individual diastereoisomeric compounds into the optically active starting materials.

Particularly suitable racemates for resolution into the antipodes are those which possess an acid group, e.g. the racemate of the compound of the formula Xlll. It is possible to convert other described racemates into acid racemates by simple reactions. For example, the aldehydes of the formulae IX and Xl react with a hydrazine derivative carrying an acid group, e.g. 4-(4- carboxyphenyl)-semicarbazide, to give the corresponding hydrazone derivatives, or the alcohols of the formulae IV, Vlll or X react with a dicarboxylic anhydride e.g. phthalic anhydride, to give the racemate of an acid half ester.

These acid racemates can be reacted with optically active bases, e.g. esters of optically active aminoacids, or ()-brucine, (+)-quinidine, ()-quinine, (+)-quinquonine, (+)-dehydroabietylamine, and ephedrine, (+)-and (-)-l-phenyl-ethylamine or the N- monoor dialkylated derivatives thereof, to give mixtures consisting of two diastereoisomeric salts.

The racemates cited hereinbefore which contain hydroxy groups can also be resolved into their optical antipodes, for which purpose there are used in particular optically active acids, or reactive functional derivatives thereof, which form diastereoisomeric esters with the cited alcohols. Examples of such acids are: ()-abietic acid, ,D(+)-and L( )-malic acid, N-acylated optically active aminoacids, and ()-camphanic acid, and (-)-ketopinic acid, L(+)-ascorbic acid, (+)-camphoric acid, (+)-campher-l-sulphonic acid(B), or ()-ot-bromo-camphor-1r-sulphonic acid, (D()-quinic acid, (D()-isoascorbic acid, D()- ,and L(+)- mandelic acid, (+)-l methoxyacetic acid, D()- and L(+)-tartaric acid and the di-O-benzoyl and di-O-ptoluyl derivatives thereof.

Racemates which contain hydroxy groups can be converted into a mixture of diastereoisomeric urethanes, for example by reaction with optically active isocyanates, such as or ()-1- phenylethylisocyanate.

It is possible for basic racemates, such as those of the formulae VII and VIII, to form diastereoisomeric salts with the above cited acids.

Racemates which contain double bonds can be converted, for example with platinum chloride and (+)-l-phenyl-2-aminopropane, into mixtures of diastereoisomeric complex salts.

Physicochemical methods are suitable for separating the distereoisomeric mixtures, chiefly fractionated crystallisation. But chromatographic methods can also be used, primarily solid-liquid chromatography. Readily volatile diastereoisomeric mixtures can be separated also by distillation or gas chromatography.

The resolution of the separated diastereoisomeric compounds into the optically active starting materials is also performed by conventional methods,

' The acids or bases are liberated from the salts. cg. by treatment with acids or bases which are stronger than those originally used. From the esters and urcthanes are obtained the desired optically active compounds,

for example by alkaline hydrolysis or by reduction with a complex hydride, such as lithium aluminium hydride A further method of resolving the racemates consists in chromatography on optically active absorption layers, for example on cane sugar;

According to a third method, the racemates are dissolved in an optically active solvent and the more sparingly soluble optical antipode is crystallised out.

In a fourth method, the varying reactivity of the optical antipodes to biological material, such as microorganisms or isolated enzymes, is utilised.

In a fifth method, the racemates are dissolved and one of the optical antipodes is crystallised by inoculation with a small amount of an optically active product obtained by the above methods.

The term lower used to qualify the syllable alk, e.g. in lower alkane, lower alkyl, lower alkoxy, lower alkylene and the like, indicates that the respective hy' drocarbon radicals contain up to 7 carbon atoms, but in general up to 4 carbon atoms are preferred.

The esters of the formula III which fall within the scope of the present invention, in which Z represents an esterified hydroxy group, their optical antipodes and racemates, are derived from inorganic or organic acids. Preferred esters are those of strong acids which are able to undergo the cyclisation reaction desired in the next step accompanied by the splitting off of an acid HZ,. Such esters are, for example, derived from hydrohalic acids, such as hydrochloric or hydrobromic acid, but are derived in particular from organic, e.g. aliphatic or aromatic, sulphonic acids, such as lower alkanesulphonic acids optionally substituted by halogen, e.g. methanesulphonic acid or trifluoroor trichloromethanesulphonic acid, or from benzenesulphonic acids optionally substituted e.g. by one or more lower alkyl, phenyl, or nitro groups or by halogen, for example chlorine or bromine, e.g. benzenesulphonic acid, p-toluenesulphonic acid, p-biphenylsulphonic acid, p-nitrobenzenesulphonic acid or p-bro mobenzenesulphonic acid.

Also falling within the scope of the present invention are esters of the formula lll, and the optical antipodes and racemates thereof, which are derived from weaker or weak inorganic or organic acids. These esters are less suitable for the cyclisation reaction desired in the next step, but they can be used for example for the purification and/or characterisation of the carbinol falling under the formula III, and the optical antipodes or racemates thereof. Such esters are, for example, derived from boric acid, sulphurous acid, phosphorous acid, phosphoric acid, carbonic acid, e.g. of carbonic acid which is monoesterified with tert. butanol, 2-methylbutan-2-ol, a,a-dimethyl-p-phenylbenzyl alcohol, oz-phenylbenzyl alcohol, trichloroethanol, 2-iodoethanol or benzoylmethanol, or which is monosubstituted with an amine, e.g. a lower alkylamine opitionally substituted by phenyl, from xanthogenic acids, in particular from lower alkylxanthog'enic acids, e.g. methylxanthogenic acid, also from aliphatic monocarboxylic acids, for example from lower alkanecarboxylic acids optionally substituted by halogen, e.g. acetic acid, propionic acid, butyric acid, or trifluoroor trichloro acetic acid, from aliphatic dicarboxylic acids, such as oxalic acid or malonic acid, from aromatic carboxylic acids such as benzoic acids which are optionally substi tuted by one or more alkyl, phenyl or nitro groups or by halogen e.g. bcnzoic acid, p-methylbenzoic acid, p biphenylcarboxylic acid, p-nitrobenzoic acid or pchlorbcnzoic acid, or also from aromatic dicarboxylic acids, eg from optionally substituted benzenedicarboxylic acids such as phthalic acid.

Also to be highlighted are the esters derived from the optically active acids cited hereinbefore and which are suitable for resolving the racemic mixture consisting of the hydroxy compound falling under the formula Ill and its optical antipode.

I A compound of the present invention, the optical antipode and racemate thereof, are manufactured by eliminating from a compound of the formula II z cn -o Z2 (11) in which Z, represents a free or esterified hydroxy group and Z represents an esterified hydroxy group, the molecule Z -H, and, if desired, converting a resulting compound within the compass of the final products and/or resolving the resulting racemate, if desired, into the optical antipodes.

In the elimination of Z -I-I, a start is made preferably from the diesters falling under the formula II, wherein Z represents an ester group with the readily eliminable strong acids defined hereinbefore under the formula III for Z,, and Z, represents an ester group with the strong or weak acids defined hereinbefore. The elimination of Z I-I is effected advantageously with basic agents, for example with organic nitrogen bases such as tertiary aliphatic amines, e.g. lower alkylor lower alkyl-cycloalkylamines such as triethylamine, ethyl diisopropylamine, ethyl-dicyclohexylamine, quaternary ammonium salts, e.g. tetralower alkyl ammonium fluorides, such as tetra-n-butyl-ammonium fluoride, nitrogen-containing basic heterocycles, such as pyridine, quinoline, N-methyl-morpholine, or bicyclic amidines, such as l,5-diazabicyclo[5,4,01undec--ene or l,5-diazabicyclo[3,4,01non-5-ene or also alkali lower alkanolates, such as lithium, sodium or potassium tert. butylate. Preferred bases are alkali or alkaline earth hydroxides, e.g. potassium hydroxide.

It is also possible to start from a compound of the formula Ill, wherein Z represents a hydroxy group esterified with a xanthogenic acid, e.g. methylxanthogenic acid. The xanthogenic acid is split off to form the bouble bond by pyrolysing the corresponding compound, e.g. by distillation under atmospheric pressure in the presence of an alkali carbonate, such as sodium carbonate.

It is also possible, however, to start from a monoester falling under the formula III, wherein Z, represents the hydroxy group and Z represents a hydroxy group esterified with one of the readily eliminable strong acids or alkylxanthogenic acids defined hereinbefore. The reaction is carried out as explained hereinbefore in the case of the diesters.

The elimination is advantageously carried out in a solvent, it being possible to use as solvent an excess of an optionally employed liquid basic agent. In particular, it is possible to use solvents which are inert under the reaction conditions, for example hydrocarbons, such as benzene or toluene, ethereal liquids, such as dilower alkyl ethers, e.g. diethyl ether, ethylene glycol di-lower alkyl ethers, e.g. ethylene glycol dimethyl ether or ethylene glycol diethyl ether, diethyleneglycol-dialkyl ethers, e.g. diethylene glycol diethyl ether, tetrahydrofuran or dioxan, esters, such as lower alkyl esters of acetic acid, amides, such as dimethyl formamide and dimethyl acetamide, or sulphoxides, such as dimethyl sulphoxide. The alkali or alkaline earth hydroxides are preferably used in alcohols, e.g. in lower alkanols, for example in ethanol or isopropanol, or in water.

Depending upon the reagents used, the reaction can be carried out at reduced or elevated temperature, for example between about 0C and C. A preferred temperature is one between about room temperature and the boiling point of the solvent employed.

In the synthesis according to the present invention there is formed the racemic mixture consisting of a compound of the formula III and its optical antipode. The separation into the two optical antipodes can be effected by one of the methods previously described hereinbefore. An optically active synthesis is possible if a start is made from compounds of the formula II, in which Z, and/or Z are hydroxy groups esterified with optically active acids, and/or if the elimination of Z I-I takes place in an optically active solvent and/or with an optically active base.

Within the compass of the final products it is possible to convert a free hydroxy group Z, by a suitable esterification method into an esterified hydroxy group and to convert this latter by transesterification into another esterified hydroxy group or by saponification into a free hydroxy group, Suitable esterification methods are those cited hereinbelow in connection with the manufacture of the starting material of the formula II. The transesterification action can be effected by one of the esterification methods described with a substantial excess of the desired functional acid derivative. The saponification takes place preferably in alkaline medium with, in particular, the compounds of the formula III, in which Z, represents a hydroxy group esterified with a weak acid.

The process also comprises those embodiments wherein compounds occurring as intermediate products are used as starting materials and the remaining steps are carried out therewith, or the process is discontinued at any stage; starting materials can also be used in the form of derivatives or formed during the reaction.

Preferred starting materials and reaction conditions are those which lead to the compounds cited at the outset as being particularly preferred.

The starting materials of the formula II required for the manufacture of the compounds of the present invention are likewise new.

The manufacture of the compound of the formula II, wherein Z, and Z are hydroxy groups, can be carried out for example according to the second step of the multistep process exemplified at the outset.

The reaction of this compound to give the esters which also fall under the formula II is carried out with the acids cited hereinbefore, or, preferably, with their reactive functional derivatives, advantageously in the presence of acid binding agents. Reactive functional derivatives are primarily simple or mixed anhydrides of the cited acids. Of the mixed anhydrides, the chlorides and bromides are particularly suitable. As examples there may be cited: aliphatic or aromatic sulphonic acid chlorides, bromides and anhydrides, in particular methanesulphonic, trifluoromethanesulphonic, benzenesulphonic, p-tolucnesulphonic, p-biphenylsulphonic, p-nitrobenzenesulphonic and p-bromobenzenesulphonic chloride, and the corresponding anhydrides and bromides; also acetic, propionic, butyric, trifluoroacetic benzoic, p-chlorobenzoic, pmethylbenzoic, p-phenylbenzoic and p-nitrobenzoic chloride, and the corresponding bromides and anhydrides.

By simple anhydrides are meant those of the respective acids with themselves, for example acetic anhydride, or also internal anhydrides, for example phthalic anhydride or also ketene.

Suitable for the esterification with hydrohalic acids are in particular the halides of sulphurous acid, such as thionyl chloride, of phosphorous acid, such as phosphorus trichloride, of phosphoric acid, such as phosphorus pentachloride and phosphoroxy chloride, and of cyanuric acid, such as cyanuric chloride, and the corresponding bromides.

Carbon disulphide, which leads to the derivatives of dithiocarbonic acid, can be used as anhydride of dithio carbonic acid. The cited xanthogenates can thus be manufactured by treating an alkali metal salt, e.g. the sodium salt of a hydroxy compound falling under the formula II, firstly with carbon disulphide and subsequently with a lower alkyl halide, e.g. methyl iodide.

Further reactive functional derivatives of the cited acids are their esters for example of lower alkanols, or in particular their activated esters, such as the phenyl estcrs which are optionally substituted by one or more nitro groups, cyanmethyl esters or the esters of N- hydroxyphthalimide.

As acid binding agents there are used inorganic bases, such as salts of alkali or alkaline earth metals with weak acids, for example alkali or alkaline earth carbonates such as sodium, potassium or calcium carbonate, or the corresponding bicarbonates, or organic bases, preferably tertiary aliphatic or aromatic amines, such as tri-lower alkylamines, e.g. triethylamine, diisopropylethylamine, dicycloalkyl-lower alkylamines, e.g. dicyclohexylamine, and di-lower alkyl anilines, e.g. dimethyl aniline, nitrogen-containing heterocycles, such as pyridine, lower alkylpyridines and N-lower alkylpiperidine or morpholine, or amides, such as dimethyl formamide or dimethylacetamide or hexamethylphosphoric acid triamide, or basic ion exchangers. Strong bases are used advantageously in approximately stoichiometric amounts, and weak bases in excess.

As solvents it is possible to use an excess of the liquid acid binding agents cited hereinbefore. Advantageously, however, the process is carried out in a diluent which is inert under the reaction conditions, for example in the ethereal liquids cited hereinabove, in hydrocarbons, such as toluene, or benzene, in chlorinated hydrocarbons, such as methylene chloride or chloroform.

The esterification can be carried out at reduced or elevated temperature, preferably between about 30 and 100C.

By using equimolar amounts of the compounds of the formula 11, wherein Z and Z are hydroxy groups, and of the reactive acid derivative, there is obtained preferably a monoester of the formula 11, wherein Z represents an esterified hydroxy group and Z represents a free hydroxy group. On the other hand, by using two equivalents of the reactive acid derivatives, there are obtained diesters of the formula ll, in which both bydroxy groups are esterified with the same acid.

Diesters of the formula II, in which Z and Z are difi ferent, are obtained by converting the hydroxy group Z of a monoester obtained above into an ester group which is different from Z If Z is an ester group which can be saponified more easily than Z for example one of the carbonic acid ester groups cited hereinbefore, it is possible to obtain by partial saponification of Z and maintaining the ester group Z a monoester, in which Z represents the hydroxy group and Z represents an esterified hydroxy group.

The following Examples illustrate the invention, without in any way being limitative thereof.

EXAMPLE 1 A mixture of 1.056 g (8 mmols) of cis-cyclohexane- 1,3,5triol, 1.072 g l 1.6 mmols) of glyoxylic monohydrate, 2.0 g 10.5 mmols) of p-toluenesulphonic monohydrate, 50 ml of benzene and 10 ml of water is boiled under reflux for 16 hours in a Dean-Stark steam trap. After the reaction solution has cooled, it is decanted off from a small amount of undissolved resin, washed with 20 ml of a solution which is saturated with sodium chloride and sodium bicarbonate, and with 35 ml of water. The combined washings are extracted with methylene chloride and the methylene chloride layer is combined with the benzene solution, dried over sodium sulphate and concentrated in a water jet vacuum. The residue is recrystallised from methylene chloride/ether to give 2,-

5,11-trioxatricyclo[4,3,1,l ]undecan-3one of the formula la 0 o W (Ia) which melts at 143C.

EXAMPLE la While stirring, 10.56 g (0.08 mols) of cis-cyclohexane-1,3,5-triol and 10.72 g (0,116 mols) of glyoxylic monohydrate in 400 ml of ethylene glycol dimethyl ether are heated until all is dissolved. To the cooled solution are added carefully 96 g of Amberlyst l5 (strongly acid catalyst in pearl form, Rohm and Haas Co.) [dried for 4 hours at l 10C and 0.05 Torr]. The resulting suspension is boiled under reflux for 30 minutes, cooled and filtered. The Amberlyst 15 which is filtered off is washed twice with 60 ml of ethylene glycol dimethyl ether each time and then with 1000 ml of methylene chloride. The filtrate is combined with the washings and extracted with 400 ml of normal sodium bicarbonate solution.'The sodium bicarbonate solution is washed with 300 ml of methylene chloride, the methylene chloride solution is combined with the previously obtained organic solutions and these are dried over sodium sulphate and evaporated in a water jet vacuum. The crystalline residue is recrystallised from methylene chloride/ether to give 2,5,1 1-trioxatricyclo[4,3,l ,l" "]undecan3one of the formula la (m.p. 140l43C).

EXAMPLE lb A mixture of 500 mg (0.378 mmols) of cis-cyclohexane-l,3,5-triol and 920 mg (0.567 mmols) of methyl diethoxyacetate in ml of ethylene glycol dimethyl ether is heated under reflux, treated after 15 minutes with 2 g of predried Amberlyst 15 (see Example 1a) and boiled for a further 10 hours under reflux with stirring. The catalyst is filtered off hot and washed twice with 20 ml of methylene chloride. The filtrateis concentrated under reduced pressure, the residue is taken up in the combined methylene'chloride fractions and the resulting solution is shaken with 10 ml of water. The isolated aqueous layer is extracted with 10 ml of methylene chloride and the combined methylene chloride fractions are dried with anhydrous sodium sulphate and the solvent is distilled off. The crystalline residue is treated with 2 ml of ether and the crystalline 2,-

5,11-trioxatricyclo[4,3,l,l ]undecan-3-one of the formula la is collected by suction filtration (m.p. 140l43C).

EXAMPLE 2 a. Analogous to Example 1, the 2,5,11- trioxatricyclo[4,3, l l ]undecan-3-ol of the formula lb is obtained from the glyoxal hydrate and cis-cyclohexane-l,3,5-triol. Melting point: l85l04C.

b. To a stirred solution of 340 mg of 3,5,1-1- trioxatricyclo[4,3,l ,1 ]undecan-3-one are added dropwise within 10 minutes under nitrogen and at room temperatre, 2.8 ml of a 20% solution of diisobutylaluminium hydride in toluene. After a further 30 minutes at room temperature the reaction mixture is shaken with 0.8 ml of water and 2 g of silica gel for 15 minutes and, upon addition of 8 g of sodium sul phate, filtered through a glass filter. The filter cake is extracted with a small amount of methylene chloride. The solvent is distilled off from the combined filtrates under reduced pressure to give pure 2,5,1 1- trioxatricyclo[4,3,l,1 "]undecan-3-ol of the formula lb, which melts at 185l 94C (sublimation at 145C).

c. A solution of 340 mg of 2,5,1 l-trioxatricyclo[4,3,1,l ]undecan-3-one in 10 ml of absolute ethanol is treated with 300 mg of sodium. After the metal has dissolved the reaction mixture is treated with 10 ml of water and 0.7 ml of acetic acid, concentrated under reduced pressure to about 3 ml and the concentrate is extracted with methylene chloride. The solvent is evap orated to leave as residue pure 2,5,1 l-trioxatricyclo- [4,3,1 ,l ']undecan-3-ol.

EXAMPLE3 A solution of 8.50 g (0.05 mols) of 2,5,11- trioxatricyclo[4,3,l ,l']undecan-3-one of the formula la in 90 ml of ethylene glycol dimethtyl ether is added HO-Cl-l +o dropwise within 15 minutes, while stirring and cooling with ice, to a suspension of 2.0g (0.05 mols) of lithium aluminium hydride in 60 ml of ethylene glycol dimethyl ether. The reaction mixture is boiled for 15 minutes under reflux, cooled to room temperature and carefully treated with 10 ml of ethyl acetate to destroy excess lithium aluminium hydride. Then, while stirring, 2.0 ml of water, 2.0 ml of 15% sodium hydroxide solution, and finally 6 ml of water, are added to the reaction mixture. The precipitated salts are filtered off, stirred with ml of methylene chloride and filtered again. The combined filtrates are concentrated in a water jet vacuum. The crystalline residue is recrystallised from methylene chloride to give 3-hydroxymethyl-2,4- dioxabicyclo[3,3,l lnonan-7-ol of the formula Ila OH (Ila) m.p. 149151C.

EXAMPLE 3a A solution of 340 mg of 2,5,] l-trioxatricy clo[4,3,1,1lundecan-3-one of the formula la in 10 m] of absolute ethanol is treated at room temperature with 150 mg of sodium borohydride and the mixture is stirred for 2 hours. The reaction mixture is diluted with 10 ml of water, the pH adjusted to 8 with a few drops of glacial acetic acid and the resulting solution is concentrated under reduced pressure to about 3 ml. The concentrate is extracted three times with altogether 100 ml of methylene chloride, the combined extracts are dried with sodium sulphate and the solvent is distilled off to give 3-hydroxymethyl-2,4- dioxabicyclo[3,3,l]nonan-7-o1 of the formula Ila, which melts at 146l49C.

EXAMPLE 3b A similar 3 hour reduction of 340 mg of 2,5,11- trioxatricyclo[4,3,l,l ]undecan-3-one of the formula la in 10 m1 ofisopropanol with 150 mg of sodium borohydride at 50C, and subsequent working up as described hereinabove, leads to the same compound of the formula Ila.

EXAMPLE 3c To a solution of 340 mg (Zmmols) of 2,5,1 1- trioxatricyclo[4,3,1,l lundccan-3-one in 10 ml of methanol are added all at once 150 mg of sodium borohydride while stirring and cooling to l2-15C(water bath). After 1% hours, during which time the bath temperature is allowed to rise to 20C, a further 150 mg of sodium borbhydride are added and the mixture is stirred for 2%. hours at 20C. The reaction mixture is then treated with 10 ml of water, the pH adjusted to 8 with a few drops of acetic acid, and concentrated under reduced pressure to about 3 ml. The concentrate is ex tracted three times with 25 ml of methylene chloride on each occasion, the combined extracts are dried over sodium sulphate and the solvent is distilled off (at the conclusion under reduced pressure) to give crystalline 3hydroxymethy1-2,4-dioxabicyclol3,3,1lnonan-7-ol of the formula Ila (m.p. l46149 C).

' EXAMPLE 4 of ether on'each occasion. The last ethereal extract is washed with 50 ml of water and each organic extract is finally washed with 50 ml of concentrated sodium chloride solution. The organic solutions are dried over 5 magnesium sulphate and evaporated in a water jet vacuum.

Chromatography of the residue on basic aluminium oxide (activity level IV) with benzene as eluant results in a racemic mixture of 3-methylsulphonyloxymethyll 2,4-dioxabicyclo[3,3,1]non-6-ene of the formula Illa I A solution of 0.87 g mmols) of 3-hydroxymethyl -2,4-dioxabicyclo[3,3,l ]nonan-7-ol of the formula 11a in 5 ml of anhydrous pyridine is cooled to -20C and, while stirring, treated with 1,1 ml 14,2 mmols) of methanesulphonyl chloride. The cooling bath is removed and the reaction mixture is added after 1% hours to 40 ml of a normal sodium bicarbonate solution. The resulting mixture is extracted successively with 40 ml of ethyl acetate and 40 ml of methylene chloride. The combined organic solutions are washed with ml of sodium bicarbonate solution, dried over magnesium sulphate and concentrated in a water jet vacuum. The crude product is recrystallised from acetone/heptane I and gives 7- methylsulphonyloxy-3- CH 50 o c H methylsulphonyloxymethyl-2,4-dioxabicyclo[ 3 ,3,1 ]no- 3 2 nane of the formula llb I H H I H SO O-CH L mp. 137 C. and its optical antipode, with a melting point of 5 9 EXAMPLE 5 4 5 C To a solution of 348 mg (2 mmols) of 3- EXAMPLE 6a hydroxymethyl-2,4-dioxabicyclo[3,3,l]nonan-7-ol of A solution of 660 mg of 7-methylsulphonyloxy-3- the formula lla in 2.0 ml of absolute pyridine are added methylsulphonyloxymethyl-2,4-dioxabicyclo[3,3,1]noat 15C with stirring 1.28 g of p-bromobenzenesulnane of the formula llb and 1.4 g of tetrabutylamphochloride all at once and the resulting mixture is furmonium fluoride in 7.5 ml of dimethyl formamide is ther stirred under nitrogen for 48 hours at room temheated under nitirogen for 7 hours to 60C. The cooled perature. The reaction mixture is treated with 25 ml of reaction mixture is treated with 20 ml of methylene methylene chloride and shaken succesively with 15 ml chloride and 80 ml of ether and shaken successively of 8% NaHCO}, and 15 ml of sodium chloride solution. with 80 ml of an 8% sodium bicarbonate solution, 100 The aqueous layers are extracted on e more with methml of water and 50 ml of sodium chloride solution. The ylene chloride. The combined organic phases are dried aqueous layersare extracted separately twice with 100 over sodium sulphate and freed from solvent and pyriml of the same solvent mixture on each occasion. The dine in a water jet vacuum and finally in an oil pump, combined organic fractions are dried over sodium sulto leave as residue crude 7-(p- 40 phate. The solvent is distilled off. under reduced presbromophenylsulphonyloxy)-3-(psure to give an oily product whose spectrum properties bromophenylsulphonyloxymethyl)-2,4-dioxabicycorrespond to those of the pure racemic 3- clo[3,3,l ]nonane of the formula llc methylsulphonyloxymethyl-2,4-dioxabicyclo[3,3,l

i H H B'r- -SO-O-CH 0 oso -Br 2 2 y V 2 (llc) which congeals to a crystalline solid on standing. It is non-6-ene of the formula llla. Preparative chromatogcrystallised from boiling benzene with the addition of raphy on the basis aluminium oxide with benzene as ela small amount of hexane. Melting point: 128C; the uant gives crystalline product of melting point crystals contain mols of benzene. 5356C.

EXAMPLE 6 EXAMPLE 6b A solution of 1.65 g (5 mmols) of 7- A mixture of 300 mg' (0.91 mmols) of 7- methylsulphonyloxy-3-methylsulphonyloxymethyl-2,4- methylsulphonyloxy. 3-methylsulphonyloxymethyl-2,4- dioxabicycloi3,3,l ]nonane of the formula llb and 3.0 dioxabicyclo[3,3,l ]nonane of the formula llb and 15 ml (20 mmols) of l,5-diazabicyclo[5,4,0]undec5-ene ml of anhydrous toluene is heated to C and treated in 25 ml of anhydrous dimethyl sulphoxide is heated for within 2 hours in 5 amounts of altogether 300 mg of po- 45 minutes to l 10C. The reaction mixture is cooled to tassium tert.butylate dissolved in 5 ml of tert.butanol. room temperature and then diluted with 150 ml of The reaction mixture is stirred for a further 2 hours. ether. It is then washed successively with 75 ml of Zn then cooled, treated with saturated sodium chloride sohydrochloric acid, ml of water and finally with 100 lution and extracted 5 times with 10 ml of methylene ml of normal sodium bicarbonate solution. The aquechloride on each occasion. The combined organic exous layers are extracted separately twice with ml tracts are washed once more with saturated sodium chloride solution, dried over magnesium sulphate and concentrated. Preparative chromatography of the resulting residue on silica gel with ethyl acetate as eluant yields a racemic mixture consisting of 3- methylsulphonyloxymethyl-2,4-dioxabicyclo[ 3 ,3 ,1 non-6-ene of the formula llla and its optical antipode of melting point 5058C.

EXAMPLE 6c A solution of 60mg(0,l8 mmoles) of 7- methylsulphonyloxy-3-methylsulphonyloxyethyl-2,4- dioxabicyclo[3,3,1]nonane of the formula llb in 3 ml of ethylene glycol dimethyl ether (filtered through basic aluminium oxide) is heated to 80C and treated with a solution of 60 mg (0.54 mmols) of sublimed potassium ten. butylate in 0.7 ml of tert.butanol The reaction mixture is cooled after 4 hours, treated with a saturated sodium chloride solution and extracted 5 times with 6 ml of methylene chloride on each occasion. The organic phases are dried over magnesium sulphate, and the solvent is evaporated. Preparative layer chromatography on silica gel with ethyl acetate as eluant yields a racemic mixture consisting of 3- methylsulphonyloxymethyl-2,4-dioxabicyclo[ 3 ,3 ,1 non-6-ene and its optical antipode.

EXAMPLE 6d A solution of 80mg(0,24 mmoles)7 methylsulphonyloxy-3-methylsulphonyloxy-methyl- 2,4-dioxabicyclo[3,3,l]nonane of the formula llb in 2 ml of dimethyl sulphoxide (which has been dried over calcium hydride) is treated dropwise within minutes with a solution of 100 mg of potassium tert. butylate (0.89 mmols) in 3 ml of dimethyl sulphoxide. The reaction temperature is kept at C. The reaction mixture is then diluted with 10 ml of ether and washed with 8 ml of 0.5 n hydrochloric acid and 10 ml of saturated sodium bicarbonate solution. The aqueous layers are extracted twice with 10 ml of ether on each occasion. The combined organic phases are washed again with 5 ml of sodium bicarbonate solution and 10 ml of water, dried over magnesium sulphate and concentrated in vacuo to give a racemic mixture consisting of 3- methylsulphonyloxymethyl-2,4-dioxabicyclo[ 3,3,1 non-6-ene of formula 111a and its optical antipode.

EXAMPLE 6e A solution of 100 mg (0.3 mmols) of 7- methylsulphonyloxy-3methylsulphonyloxymethyl-2,4- dioxabicyclo[3,3,l ]nonane of the formula llb in 5ml of tert.butanol (distilled over calcium hydride) is heated to 80C and 60 mg (0.54 mmols) of sublimed potassium tert.butylate dissolved in 2 ml of tert.butanol are added within 1 hour. The reaction mixture is heated for 6 hours at the same temperature, and then a further 110 mg. (0.1 mmols) of potassium tert.butylate, dissolved in 0.5 ml of tert.butanol are added. The reaction mixture is heated for a further hour, cooled, treated with 40 ml of ether and washed 5 times with 15 ml of -SO O- CH water each time. The organic phase is dried over magnesium sulphate and evaporated to give a racemic mixture consisting of 3-methylsulphonyloxymethyl-2,4- dioxabicyclo[3,3,l ]non-6-ene of the formula Illa and its optical antipodes, in the form of a colourless oil which crystallises on standing and is sufficiently pure for use in the following reaction.

EXAMPLE 6f 7-methylsulphonyloxy-3-methylsulphonyloxymethyl- 2,4-dioxabicyclo[3,3,l ]nonane (280 mg) is added to 5 ml of a boiling 2n potassium hydroxide solution in absolute alcohol and the mixture is boiled for 2 minutes under reflux while stirring vigorously. The reaction mixture which has congealed to a crystalline solid is cooled and, after treatment with 5 ml of 8% sodium bicarbonate solution, extracted three times with methylene chloride. the combined extracts are dried with sodium sulphate and the solvent is distilled off under reduced pressure to leave as residue the crystalline racemic 3-methylsulphonyloxymethyl-2,4-dioxabicycl0[3,3,l ]non-6-ene (m.p. 53-56).

EXAMPLE 6g To a hot suspension of 280 mg of 7- methylsulphonyloxy-3-methylsulphonyloxymethyl-2,4- dioxabicyclo[3,3,l ]nonane in 2,5 ml of isopropanol is added 2,5 ml of a boiling 2 n potassium hydroxide solution in isopropanol while stirring vigorously, and the resulting reaction mixture is boiled under reflux for 3 minutes. The reaction mixture is cooled and treated with 5 ml of an 8% sodium bicarbonate solution, then extracted 3 times with methylene chloride. The combined extracts are dried over sodium sulphate and the solvent is distilled off in vacuo under reduced pressure to leave as residue the racemic 3- methylsulphonyloxymethyl-2,4-dioxabicyclo[ 3 ,3 ,1 non6-ene in the form of a colourless oil, which soon congeals to a crystalline solid (mp. 53-56C).

EXAMPLE 7 A solution of 61mg bromophenylsulphonyloxy)-3-(pbromophenylsulphonyloxymethyl )-2,4-dioxabicyclo[3,3,l]nonane of the formula I10 and 220 mg of tctra-n-butylammonium fluoride in 1.0 ml of anhydrous dimethyl formamide is heated with stirring in a nitrogen atmosphere for 45 minutes to 60C. The cooled reaction mixture is treated with 5 ml of methylene chloride and 25 ml of ether and shaken successively with 8 ml of normal sodium bicarbnate solution, 10 ml of water and 10 ml of sodium chloride solution. The aqueous phases are extracted twice with 10 ml of the same solvent mixture on each occasion. All organic phases are dried together over sodium sulphate. The solvent is distilled off under reduced pressure to yield a racemic mixture consisting of 3-(pbromophenylsulphonyloxymethyl )-2,4-dioxabicyclo[3,3,l ]non-6ene of the formula lllb of 7-( p- (lllb) and its optical antipode; m.p. 1 141 17C.

EXAMPLE 8 A solution of 363 mg (1.55 mmols) of racemic 3- methylsulphonyloxymethyl-2,4-dioxabicyclo[3,3,l non-6-cne and,2l5 mg (1.55 mmols) of potassium carbonate in 3.6m] of acetone and 18 ml of water is stirred in a nitrogen atmosphere extracted 3 times with 30 ml of methylene chloride on each occasion.

The combined methylene chloride layers are concentrated, the residue is taken up in ethyl acetate and filtered through a column of 10 g of basic aluminium oxide (activity level IV). Elution is performed with ethyl acetate. Concentration of the first 60 ml of eluate in a waterjet vacuum yields a racemic mixture of 9,10- dioxatricyclo[4,3,1,0"']decan-4B-ol of the formula IVa A solution of 75 mg (0.32 mmols) of racemic 3- methylsulphony1oxymethyl-2,4-dioxabicyclol 3,3,1 non-6-ene of the formula Illa and 44 mg (0.32 mmols) of potassium carbonate in 0.5 ml of ethylene glycol dimethyl ether and 2.5 ml of water, is stirred for 18 hours under reflux in an oil bath which is kept at 100C. The cooled reaction solution is diluted with water, saturated with NaCl and extracted times with 10 ml of methylene chloride on each occasion. The combined extracts are dried over magnesium sulphate and concentrated. The residue is resolved by means of preparative layer chromatography (on silica gel, cluant: methylene chloride/acetone 1:1 A racemic mixture of 9,10 dioxatricyclo[4,3,1,0 ]decan-4B-ol of the formula IVa and its optical antipode is obtained.

(IVa) EXAMPLE 8b To a well stirred suspension of 16.5g (0.05 mols) of racemic 7-methylsulphonyloxy-3- methylsulphonyloxymethyl-2,4-dioxabicyclo[3,3,1]nonane in 125 ml of boiling isopropanol is added a hot solution of 14 g of potassium hydroxide (0.25 mol) in 125 ml of isopropanol in one amount. In a few seconds a clear solution temporarily forms from which, however, potassium mesylate soon begins to precipitate. After stirring vigorously for 3 minutes at the boiling temperature of the solvent, the reaction mixture which in the meantime has congealed to a crystalline solid is treated with a solution of 25 g of potassium bicarbonate in 1250 ml of water and about 250 ml are distilled off under reduced pressure from the resulting clear solution. The reaction mixture is then brought to the original volume by adding water and boiled under reflux for 16 hours in a nitrogen atmosphere. It is then cooled, saturated with sodium chloride and repeatedly extracted with methylene chloride. The combined extracts are dried over sodium sulphate and the solvent is distilled off under reduced pressure to give the crystalline racemic mixture of 9,10-dioxatricyclo[4,3,l,0']decan-4B-ol and its optical antipode. In similar manner it is also possible to use a 2n solution of potassium hydroxide in ethanol or in water/ethylene glycol monomethyl ether (2:1) for the splitting off of the methanesulphonic acid. The product can be further used without purification or purified as follows via its acetate:

A solution of 1.46 g of the racemic 9,10-dioxatricycl0[4,3,1,0ldecan-4B-ol in 25 ml of pyridine and 8 ml of acetic anhydride is allowed to stand for 14 hours at room temperature and then evaporated in a high vacuum. The residue is recrystallised from diethyl ether to give the pure racemic 4B-acetoxy-9,10-dioxatricyclo[4,3, l ,0 '*]decane which melts at 9798C.

A solution of 198 mg of the pure racemic 4B- acetoxy-9,l0-dioxatricyclo[4,3,1,0 ]decane in 8 ml of ethanol and 2 ml of Zn aqueous potassium hydroxide is boiled under reflux for 1 hours in a nitrogen atmosphere. The ethanol is then distilled off in vacuo and the residue is extracted 4 times with 20 ml of methylene chloride on each occasion. The methylene chloride solutions are evaporated and the pure 9,10-dioxatricyclo[4,3,1,0"- ]decan-4B-ol is obtained, which after recrystallisation from benzene/cyclohexane melts at 250256C (sealed capillary).

EXAMPLE A solution of 1.56 g (10.0 mmols) of the pure racemic 9,1O-dioxatricyclo[4,3,1,0 ]decan-4B-o1 (purified via the acetate) in 15 ml of pyridine is treated, while stirring, with 2.50 g( 12.5 mmols) of (S)- ketopinylchloride (prepared from S-ketopininc acid with thionyl chloride/pyridine. S-ketopinic acid is prepared from (+)-10-camphorsu1phonic acid monohydrate analogous to the process described in Organic Syntheses 45, 14, 55). The reaction mixture is stirred for 18 hours at room temperature and added to a mixture of 25 m1 of saturated sodium carbonate solution and 25 ml of water. The mixture is extracted 3 times with 50 m1 of methylene chloride on each occasion. The methylene chloride solution is treated with benzene, then evaporated in vacuo, and the residue recrystallised 4 times from ethyl acetate to give the pure 88- 4B-( S-ketopinyloxy)-9, l 0-dioxtricyc1o[ 4,3 ,1 ,0 ]decane, [04],, 47 (c'=l in chloroform) which melts at 183185C. The mother liquor contains the crude 8R- 4,8-(S-ketopinyloxy)-9,10-dioxatricyclo[4,3 ,1,0 decane which melts at 111-] 14C. A solution of 1.28 g (4.0 mmols) of the pure 8S-4B-(S-ketopinyloxy)- 9,l0-dioxatricyclo[4,3,l ,0* ]decane and 8.0 m1 of 2 n aqueous potassium hydroxide in 32 ml of ethanol is boiled under reflux for 15 hours in a nitrogen atmosphere. The solution is then cooled, the ethanol evaporated in vacuo, the residue treated with 5ml of water and extracted 6 times with 50 ml of methylene chloride on each occasion. The combined methylene chloride layers are evaporated, and the residue is first sublimed at l 10C (0.02 Torr) and then recrystallised from benzene/cyclohexane. The pure 8S-9,1()-dioxatricyclo[4,3,l,0 ldecan-4B-ol of the formula lVa melts at 251256C, lulu -147 (c 1 in chloroform).

EXAMPLE 8d A solution of 1.56 g 10.0 mmols) of the racemic 9,1-

-dioxatricyclo[4,3, l ,0'*]decan-4[3-ol (purified via the acetate) in 30 ml of dry benzene is boiled for 14 hours under reflux with 1 ml of triethylamine and 2.2 g (15 mmols) of ()-1-phenyl-ethylisocyanate. After evaporation in vacuo and drying in a high vacuum at 50C the residue is crystallised out from ethyl acetate/hexane and recrystallised times from benzene. The resulting pure urethane melts at 144-145C and has the following optical rotation: [Q =32 (c 1 in chloroform). This urethane (50 mg) is boiled under reflux with 1.0 ml of 2n potassium hydroxide solution in ethanol. The mixture is then treated with water 10 ml) and concentrated to 5 ml. The solution is washed 3 times with ml of pentane on each occasion, then concentrated to 1 ml and the concentrate is extracted 5 times with 20 ml of methylene chloride on each occasion. The combined methylene chloride solutions are filtered through cotton wool and evaporated. The residue, 8S-9,l0- dioxatricyclo[4,3,1,O ]decan-4B-ol, has the optical rotation [01]" 147 (c 1 in chloroform).

In analogous manner it is possible to obtain the 8R- 9,l0-dioxatricyclo[4,3,1,0 ]-decan-4B-ol with the optical rotation [a],,=+l47 (c 1 in chloroform) from the pure racemic 9,10-dioxatricyclo[4,3,1,01decan- 43-01 with the aid of (+)-1-phenyl-ethylisocyanate.

EXAMPLE 8e A solution of 100 mg of the racemic 4B, 5B-epoxy-9, 10-dioxatricyclo[4,3, 1 ,0 decane in 3ml of dry tetrahydrofuran is boiled under reflux for 14 hours with 200 mg of lithium aluminium hydride. The mixture is then cooled 0.2 ml of water, 0.2 ml of 2n sodium hydroxide solution and 0.6 ml of water are added and the resulting suspension is stirred for 1 hour at room temperature. It is then filtered with suction and the precipitate is washed 3 times with 15 ml of methylene chloride on each occasion. The organic solutions are evaporated to yield the pure racemic 9,10-dioxatricyclo [4,3,1 ,0 ]decan4B-ol.

EXAMPLE 9 While stirring, a solution of 0.24 ml of methanesulphonyl chloride in 5.0 ml of methylene chloride is added at a temperature of 10C to a solution of 156 mg (1.00 mmols) of racemic 9,10-dioxatricyclo[4,3,1,0 ldecan-4fi-ol and 0.55ml (4.00 mmols) of triethylamine in 5,0 ml of methylene chloride. After 40 minutes, during which time the cooling bath has warmed to 0C, the reaction mixture is diluted with ml of methylene chloride and washed with 10ml of normal sodium bicarbonate solution. The sodium bicarbonate layer is washed with lOml of methylene chloride and this methylene chloride layer is combined with the previous methylene chloride solution, dried over sodium sulphate and concentrated in a water jet vacuum. The residue is taken up in a small amount of ethyl acetate and filtered through a column of 5 g of basic aluminium oxide (activity level IV). After elution with ethyl acetate and concentrating the first 50 ml of the eluate there is obtained as residue a crude racemic mixture of 4B-methylsulphonyloxy-9,l0-dioxatricyclo [4,3,1 ,0 ldecane of the formula IVb H (IVb) LII and its optical antipode, which can be used in the next reaction without further purification. However, it can also be recrystallised from ethyl acetate/pentane or ether/methylene chloride. Melting point: l02106C. In analogous manner the 8S-4B-methylsulphonyloxy- 9,l0-dioxatricyclo[4,3,l ,0"']decane of the formula IVb, which melts at 120C (with decomp.) ethyl acetate/hexane, [all] 90 (C l in chloroform), is obtained from the -9,l0-dioxatricyclo[4,3,l,O Idecan-4B-ol.

EXAMPLE 9a A solution of 550 mg (3.52 mmols) of the racemic 9,l0-dioxatricyclo[4,3,1,0 ']decan-4/3-ol in 25 ml of ether (filtered over basic aluminum oxide) is treated with 900 mg of sodium hydride (50%) and the mixture is boiled under reflux for 3 hours. Then 2 ml of carbon disuplhide are added and heating is continued for 3 hours. Finally, 2 ml of methyl iodide are added and the mixture is refluxed for a further 4 hours. The reaction mixture is cooled and excess sodium hydride is then destroyed with moist ether and subsequently with water. The organic phase is isolated and dried over magnesium sulphate. The solvent is expelled and the resulting oil is dissolved in benzene and filtered over aluminum oxide (activity level IV). After an extremely unpleasent smelling component has passed out of the column the eluate is combined and evaporated. Repeated crystallisation of the residue from heptane yields the racemic mixture consisting of 9,10-dioxatricyclo[4,3,1.0

decane-4B-methylxanthogenate of the formula IVc S ll 005C14 (IVc) M and its optical antipode; m.p. 8l82C.

EXAMPLE 10 A solution of the crude racemic 4B- methylsulphonyloxy-9,10-dioxatricyclo[4,3,l ,0 ']dec ane of the formula IVb, obtained in Example 9, in 1.0 ml of anhydrous dimethyl sulphoxide is treated in a nitrogen atmosphere and with stirring with 2,5m of a freshly prepared normal solution of potassium tert- .butylat in anhydrous dimethyl sulphoxide, and the mixture is stirred for 40 minutes. The reaction solution is then diluted with 50 ml of ether and washed 4 times with 10 ml of water on each occasion and once with 20 ml of saturated sodium chloride solution. The organic layer is concentrated, the residue taken up in a small amount of methylene chloride and the solution is filtered through a column of 2 g of basic aluminum oxide (activity level IV). After elution with methylene chloride and concentrating the first 50 ml of eluate in a water jet vacuum there is obtained as residue the racemic mixture of 9,l0-dioxatricyclo[4,3,1,0 '*]dec-4-ene of the formula V ration and its optical antipode, in the form of a wax-like sub- EXAMPLE lOa To a boiling solution of 4.68 g of racemic 4B- methylsulphonyloxy-9, l O-dioxatricyclo[4,3,l ,o ldecane in 40 ml of isopropanol is added a hot solution of 4.48 g of potassium hydroxide in the same solvent in a single amount and the resulting reaction mixture is refluxed for 2 hours with stirring. During this time the reaction mixture congeals to a crystalline solid from the precipitated potassium rnesylate. It is then treated with 100ml of 8% sodium bicarbonate solution and repeatedly extracted with methylene chloride. The combined extracts are dried over sodium sulphate andevaporated under reduced pressure. The resulting crude product is dissolved in pentane/ether (9:1 and filtered through a column filled with 100 g of aluminum oxide (activity level IV). The first 500 m1 of eluate yield after evapothe racemic mixture of 9,10-dioxatricyclo[4,3, l ,0"]dec-4-ene of the formula V, and its optical antipode.

EXAMPLE 10b To a solution of racemic 9,10- dioxatricyclo[4, 3 ,l ,0]decane-4B-methylxanthogenate in methylene chloride is added the ten fold amount of sodium carbonate and the solvent is distilled off in a rotary evaporator. The resulting composition is heated to 150C in a pyrolysis tube. The distillate which is collected contains the racemic 9,10-dioxatricyclo [4,3,1 ,O"]dec-4-ene.

EXAMPLE 1 I To a solution of 165 mg of racemic 9,10-

dioxatricyclo [4,3,1 ,0 ]dec-4-ene in 4 ml of methanol .are added, with stirring and at room temperature 865 mg of potassium bicarbonate and 740 mg of benzonitrile. To'this mixture are added at intervals of 8 hours portions each of 0.3 m1 of 30% hydrogen peroxide and stirring is continued for 10 hours. Methylene chlo- .ride ml) is then added to the reaction mixture,

which is washed with 2% sodium hydrogen carbonate solution, dried over sodium sulphate and concentrated. Benzamide which has formed is removed by crystallisation from methylene chloride/pentane. The residual oil and its antipode, (m.p. after crystallisation from ether/- pentane: l8l-l82C), and also as main product the racemic mixture of 4a,5a-epoxy-9,lO-dioxatricyclo[4,3,l,0']decane of the formula and its antipode: (mp. after crystallisation from ether/- pentane: 146l56C).

From 8S-9, l 0-dioxatricyclo[4,3, 1 ,0 dec-4-ene there is obtained in analogous manner the 8S-4oz,5ozepoxy-9, lO-dioxatricyclo[4,3,l ,0 decane Melting point: l69l7l [a],,='95 (c= l in chloroform) and the 8S-4,8,5,B-epoxy-9, l 0- dioxatricyclo[4,3,l,0' decane Melting point:

l-l82,[oz],,= -87 (c= l in chloroform) EXAMPLE 11A To a solution of 350 mg (2,53 mmols) of racemic 9, l0-dioxatricyclo[4,3,l,0 ]dec-4-ene in'45 ml of chloroform (filteredthrough aluminum oxide of activity level I) are added 1.1 g l l mmols) of finely powdered potassium bicarbonate and then, with stirring, 570 mg of m-chloroperbenzoic acid (2.8 mmols). The mixture is stirred for 40 hours'at room temperature, filtered and the filtrate is washed twice with 30 ml of a normal sodium carbonate solution on each occasion. The organic solution is filtered through cotton wool and evaporated. The residue is chromatographed on 20 g of basic aluminum oxide (activity level IV). The racemic 413,5 ,B-epoxy-9, l 0-dioxatricyclo[4,3 l ,0 ']decane is eluted as main product with petroleum ether/benzene (7:3) and the racemic 4a,5a-9,l0-dioxatricyclo[4,3 l ,0 ]decane with benzene.

EXAMPLE 1 2 A solution of 800 mg (5.2 mmols) of racemic 40:,504- epoxy-9,l0-dioxatricyclo[4,3,l,0 ]decane in 35 ml of 24% aqueous ammonia is heated in a Carius tube under nitrogen for 1 hour at C (bath temperture). Upon cooling, the contents of the tube are evaporated to dryness. The crystalline residue is taken up in methylene chloride. The solvent is evaporated to give the pure rac'emic mixture of 4B-amino-9, l O-dioxatricyclo[4,3,l ,0 ldecan-5a-ol of the formula and its optical antipode, in the form of colourless crystals (m.p. l78l80C; sublimation at about C).

In analogous manner there is obtained from the 8S- 4a,5a-epoxy-9, l O-dioxatricyclo[ 4,3, l ,O ldecane the 8S4B-amino-9, l -dioxatricyclo[4,3, l ,0"]decan-aol; m.p. 176l78, [01],, =l55 (c l chloroform).

EXAMPLE 12a A solution of 143 mg of the crude mixture of racemic 4a,5a-epoxy-9, l0-dioxatricycloin 4,3,1 ,0 ldecane and the corresponding B-epoxide in 5 ml of 24% aqueous ammonia is heated in a Carius tube under nitrogen for 1 hour to 100C (bath temperature). Upon cooling, the contents of the tube are evaporated to dryness in vacuo, the residue is dossolved in 5 ml of water, and this solution is washed twice with ml of diethyl ether on each occasion to remove unreacted flepoxide. The aqueous phase is concentrated to yield the pure racemic 4B-amino-9, l 0-dioxatricyclo[4,3,l ,O ]-decan-5ao1 (m.p. l78180C).

EXAMPLE 13 The racemic 4B-amino-9, l O-dioxatricyclo[4,3, l ,0 ldecan-5a-ol (400mg, 2.34 mmols) is dissolved in 18 ml of a 1.23% solution of hydrochloric acid in methanol and the solution is stirred under nitrogen for 2% hours at room temperature. During this time the racemic 2-exo-amino-3,4-endo-dihydroxy8- methoxy-7-oxabicyclo[4,3,0]nonane hydro-chloride begins to crystallise from the reaction solution. The resulting suspension is evaporated to dryness in vacuo and the white crystalline residue is freed from excess hydrogen chloride by addition of a few ml of methanol and distilling it off. The resulting 2-exo-amino-3,4- endo-dihydroxy-8-methoxy-7- oxabicyclo[4,3,0]nonane hydrochloride racemate, consisting of the compound of the formula 01 (VlII a) B0" "on and its optical antipode, melts at 242244C.

A solution of 35 mg of this hydrochloride in 5 ml of water is charged on to anion exchanger column (DowexlOH) and eluted with 250 ml of water. The aqueous solution is concentrated to leave as residue the free racemic 2-exo-amino3,4-endo-dihydroxy-8- methoxy-7-oxabicyclo[4,3,01nonane which melts at 96C.

From the 8S-4B-amino-9, l 0- dioxatricyclo[4.3,l,0']decan-5a-o1 there is obtained in analogous manner the 6S-2-exo-amino-3.4-endodihydroxy-8-methoxy-7-oxabicyclo[4,3.0lnonane hydrochloride; m.p. 235-6|ul,,== 1 17 (0 1 chloroform) EXAMPLE 14 A solution of 45.6 mg of racemic 9,10-dioxatricyclo [4,3,1 ,0 ""]dec-4-ene and 10 mg of p-tolucnesulphonic acid in 1.0 ml of methanol is stirred for 45 minutes at room temperature, treated with 3 ml of sodium bicarbonate solution (8%) and extracted 3 times with ethyl acetate. The combined extracts are dried over sodium sulphate and evaporated in vacuo. The oily residue is the racemic 4-endo-hydroxy-8-methoxy-7- oxabicyclol4,3,0]non-2-ene(thin layer chromatography on silica gel with ethyl acetate as eluant, Rf: 0.36) consisting of the compound of the formula and its optical antipode.

EXAMPLE 15 and its optical antipode is eluted with methylene chlo ride. Elution with ethyl acetate/methanol (9:1) yields the racemic mixture consisting of 2,3-endo-epoxy-4- endo-hydroxy-8-methoxy-7-oxabicyclo[4,3,0lnonane of the formula and its optical antipode.

EXAMPLE 15a A mixture of 51 mg of the racemic 4-endo-hydroxy- 8-methoxy-7-oxabicyclo[4,3,0]non-2-ene, 1 ml of methanol, 183 mg of benzonitrile, 217 mg of potassium bicarbonate and 34mg of 90% hydrogen peroxide is stirred at room temperature and treated after 17 and 26 hours respectively with 34 mg of 90% hydrogen peroxide on each occasion. After a further 16 hours 3 ml of water and ml of methylene chloride are added. The organic phase is isolated, extracted 3 times with 10% sodium bicarbonate solution, the aqueous extracts are reextracted 3 times with methylene chloride and the combined organic phases are dried over sodium sulphate and evaporated. The benzamide is removed from the resulting reaction product by crystallisation from methylene chloride/pentane and the residue is chromatographed on 7 g of aluminium oxide (activity level IV). Elution with methylene chloride/ethyl acetate (5:1 yields the racemic mixture consisting of 2,3-exoepoxy-4endo-hydroxy-8-methoxy-7-oxabicyclo [4,3,0]nonane and its optical antipode. Further elution with ethyl acetate/methanol (9:1) yields the racemic mixture consisting of 2,3-endo-epoxy-4-endo-hydroxy- 8-methoxy-7-oxabicyelo[4,3,01nonane and its optical antipode.

EXAMPLE b A solution of 64 mg of the racemic 4-endo-acetoxy 8-methoxy-7-oxabicyclol4,3,0]non-2-ene, 207 mg of N-bromace-tamide in 15 ml of acetone and 6 ml of water is stirred for 16 hours at room temperature and the acetone is subsequently removed in vacuo. The aqueous solution is extracted with altogether 19 ml of methylene chloride and the methylene chloride extracts are washed with 2 ml of 2% sodium thiosulphate solution, dried over sodium sulphate and evaporated. Preparative thin layer chromatography of the residue on silica gel (methylene chloride/ethyl acetate 4:1) yields a mixture of isomeric bromohydrins. This mixture is stirred for 1 hour in 2 ml of 2.5% potassium hydroxide in methanol and to the mixture are added 20 ml of water and sodium chloride until saturation is reached. The saturated solution is then extracted 4 times with 15 ml of methylene chloride on each occasion. The methylene chloride solution is dried over sodium sulphate and then evaporated. The residue is resolved analogous to Example 15a into the racemic 2,3- endo-epoxy-4-endo-hydroxy-8-methoxy7-oxabicyclo [4,3,0]nonane and the corresponding 2,3-exo-epoxy racemate.

The starting material is obtained in the following manner:

A solution of 170 mg of the racemic 4-endo-hydroxy 8-methoxy-7-oxabieyclol4,3,()]non-2-ene in 1.5 ml of acetic anhydride and 5 ml of pyridine is stirred for 5 hours at room temperature. Volatile components are distilled off in a high vacuum, again at room temperature, and the residue is treated with toluene and distillation performed once more. The oily residue is chromatographed on preparative silica gel plates with ethyl acetate. The racemic 4-endo-acetoxy8-methoxy-7- oxabicyclol4,3,0]non-2-ene is obtained as an oily product.

EXAMPLE 15c A solution of 62mg racemic 4a,50zepoxy-9,l0-

dioxatricyclo [4,3,l,0'ldecane in 6 ml of dry methanol is treated at 0C with 6 mg of p-toluenesulphonic acid and stirred at the same temperature for 1 hour. Then 50mg of fine by pulverised potassium bicarbonate are added and the mixture is stirred for 5 minutes, filtered and evaporated. The residue consists of a racemic mixture of 2,3-endo-epoxy-4-endo-hydroxy-8- methoxy-7-oxabicyclo[4,3,0]nonane of the formula Vla and its optical antipode.

EXAMPLE 16 A solution of 30 mg of the racemic 2,3-endo-epoxy- 4-endo-hydroxy-8-methoxy-7- oxabicyclo[4,3,0]nonane in 0.3 ml of dioxan and 2 m1 of 24% aqueous ammonia is heated in a sealed test tube for 1 hour to 120C. The product is evaporated in vacuo, whereupon the racemic mixture consisting of 2-exo-amino-3,4-endo-dihydroxy-8-methoxy-7- oxabicyclo [4,3,0]nonane of the formula VIII, and its optical antipode, is obtained as a colourless oil.

EXAMPLE 17 The racemic 2-exo-amino-3,4-endo-dihydroxy-8- methoxy-7-oxabicyclo[4,3,0]nonane hydrochloride(350 mg; 1.46 mmols) and 250 mg (1.84 mmols) of crystalline sodium acetate are dissolved at 0-5C in 6 m1 of 50% aqueous acetic acid. While stirring and cooling with an ice-water bath, 1.5 ml of a 3 normal sodium nitrite solution are added to the resulting solution in an argon atmosphere within 40 minutes. After a total of minutes, the reaction mixture is neutralised with a suspension of 6 g of sodium hydrogen carbonate in 12 ml of water and extracted repeatedly with methylene chloride. The combined extracts are dried with sodium sulphate and the solvent is then dis tilled off in vacuo. The oily residue is the racemic 6- exo-formyl-3-methoxy-2-oxabicyclo[3,3,0] octan-7- endo-ol, consisting of the compound of the formula I (IX a) CHO EXAMPLE 17a A solution of 25 mg (0.123 mmols) of the racemic 2-exo-amino-3,4-endo-dihydroxy'8-methoxy-7- oxabicyclo[4,3,0] nonane in 5 m1 of dry ethylene glycol dimethyl ether is treated at 0C with mg of potassium acetate while stirring, and dinitrogen tetroxide is passed into the solution slowly over the course of 10 minutes. Excess dinitrogan tetroxide is then removed by scavenging with nitrogen, the solution is treated with ml of water and 1 ml of saturated sodium carbonate solution and extracted with. methylene chloride. The organic extract is dried over sodium sulphate and then evaporated. The residue is the racemic 6-exo-formyl-3- methoxy-Z-oxabicyclo [3,3,0]octan-7-endo-ol, which consists of the compound of the formula lXa and its optical antipode.

EXAMPLE 18 OCH and its optical antipode is a yellow oil, which in the infrared zone has absorption maxima at 2.80; 2.90; 5.92; 5.98; 6.l5[.L and in the ultraviolet zone at 230m,u.. The melting point of its 7-endo-(3,5-dinitrobenzoyloxy) derivative (obtained from the above product with 3.5- dinitrobenzoyl chloride and pyridine) is 7375,5C.

EXAMPLE 1 8a A solution of 550 mg (2.96 mmols) of the freshly manufactured racemic 6-eXo-formyl-3-methoxy-2- oxabicyclo[3,3,0] octan-7-er1do-ol in 18 ml of dry ethylene glycol dimethyl ether is treated with 1.39 g (4.4 mmols) of 1-tributylphosphoranylidene-2-heptanone (b.p.l30C at 0.001 Torr.(S.:N.Finch and .I.J.Fitt- ,Tetr.Letters 1969 4639). The resulting solution is stirred under nitrogen for 2 hours at 50C and for 12 hours at room temperature, then concentrated in vacuo. The residue, the racemic 3metoxy-6-exo(3- oxo-trans-1-octenyl)-2-oxabicyclo[3,3,0] octan-7- endo-ol is purified by preparative thin layer chromatography on silica gel with ethyl acetate as eluant. (Oil,- which congrats to a crystalline solid on standing at ,m.p.8,59,5C.)

In analogous manner there is obtained from the 18-6- exo-3-methoxy-2oxabicyclo[3,3,0]octan-7-endool the lS-3-methoxy-6-exo-(3-oxo-trans-l-octenyl)-2- oxabicyclo[3,3,0]octan-7-endo-ol; m.p. ll.5"l3"C[oz],, 69il (c =l% in chloroform).

EXAMPLE l9 A solution of 50 mg (0.177 mmols) of the racemic 3-methoxy-6-exo-( 3-oxo-transl -octenyl )-2- oxabicyclo[3,3,0] octan-7-endo-ol in 9 ml of methanol is treated at 0C while stirring with a solution of 338 mg (8.95 mmols) of sodium borohydride in 3 ml of water. The solution is stirred for 17 minutes at 0C, then poured on ml of water. The resulting solution is extracted 3 times with 50 ml of chloroform on each occasion, the combined extracts are dried over magnesium sulphate, evaporated, and the residue is dried for 1 hour in vacuo at 25C and 0.1 Torr. The residual oil is separated into two fractions by preparative thin layer chromatography on silica gel with ethyl acetate as eluant. The less polar fraction consists of the racemic 3- methoxy-6-exo-( 3R-hydroxy-trans- 1 -octenyl )-2- oxabicyclo[3,3,0]octan-7-endo-ol, consisting of the compound of the formula and its optical antipode (R; on silica gel with ethyl acetate as eluant 0,25; m.p. of its his p-nitrobenzoyloxy derivative is l35-l 37.5").

From the lS-3-methoxy-6-exo-( 3-oxo-transl octenyl)2-oxabicyclo[3,3,01octan-7-endo-ol there is obtained in analogous manner the lS3-methoxy-6- exo-( 3S-hydroxy-transl -oxtenyl )-2- oxabicyclol 3,3,0 loctan-7-endo-ol; oil,

33 [a],,20==72:+:l(C =l% in chloroform), and the lS-3- methoxy-6-exo-( 3R-hydroxy-transl -octenyl )-2- oxabicyclo[3,3,01octan-7-endo-ol, m.p. S-57C, [a],,20 88il (C 1% in chloroform).

The 3-methoxy-6-exo-( SR-hydroxy-transl -octenyl 2-oxabicyclo[3,3,0loctan-7-endo-ol which occurs as by-product can be led back into the process as follows:

A solution of 50 mg of the racemic 3-methoxy-6-exo- (3R-hydroxy-transl-octenyl)-2-oxabicyclo[ 3,3,01octan-7-endo-ol in 0.78 ml of methylene chloride is stirred in a nitrogen atmosphere for 17 hours with 782 mg of active precipitated manganese dioxide (Merck, Darmstadt). The mixture is then filtered through diatomaceous earth and evaporated. The residue is the racemic 3-methoxy-6-exo-( 3-oxo-trans l -octenyl )-2- oxabicyclo[3,3,0loctan-7-endo 01.

What we claim is:

l. A racemic mixture consisting of a compound of the formula lll (III) ZCH 34 an aliphatic or aromatic sulphonic acid, and the optical antipode thereof.

2. A racemic mixture consisting of a compound of the formula Ill (III) c 1 optical antipode thereof. 

1. A RACEMIC MIXTURE CONSISTING OF A COMPOUND OF THE FORMULA III
 2. A racemic mixture consisting of a compound of the formula III
 3. A racemic mixture consisting of a compound of the formula III according to claim 2, wherein Z1 represents the methylsulphonyloxy radical, and the optical antipode thereof.
 4. A racemic mixture consisting of a compound of the formula III according to claim 2, wherein Z1 represents the p-bromophenylsulphonyloxy radical, and the optical antipode thereof. 